Amyloid precursor protein (APP) is an integral membrane protein expressed in mammalian neurons. The protein concentrates around synapses and likely is involved in neural development and synaptogenesis (Rik van der Kant and Lawrence S. B. Goldstein, Dev Cell 2015; 32(4):502-15, the disclosure of which is incorporated herein by reference). Although expression is highest during development, APP remains expressed throughout life, possibly regulating lipid reorganization during synaptic activity.
APP undergoes extensive and complex proteolytic processing to create several peptide fragments. These fragments include β-amyloid (Aβ), soluble APPα (sAPPα), soluble APPβ (sAPPβ), APP intracellular domain (AICD), c-terminal fragment 99 (C99), c-terminal fragment (C83), and P3. Of particular interest are the Aβ fragments, which are peptides typically between 30 and 51 amino acids derived from the extracellular portion of APP. The most common Aβ peptides are Aβ1-40 and Aβ1-42 (FIG. 1 and Seq. ID Nos. 1 and 2).
Common features in the neurodegenerative Alzheimer's disease (AD) are oligomerization and fibril aggregation of Aβ in the extracellular space around neuronal junctions. Some experts have suggested that soluble oligomeric forms of the peptide are causal in development of the disease (see, I. Benilova, et al. Nat. Neurosci. 2012 15, 349-357; and L. N. Zhao, et al., Int J Mol Sci. 2012 13, 7303-7327; the disclosures of which are incorporated herein by reference). Despite great efforts to research and comprehend the relationship between Aβ oligomers and AD, there are still many unanswered and challenging questions regarding this relationship.